第二代类维生素A化合物U-83836E对大鼠肿瘤坏死因子的抑制作用及内毒素性休克的逆转作用

Inhibition of tumour necrosis factor and reversal of endotoxin-induced shock by U-83836E, a 'second generation' lazaroid in rats.

作者信息

Altavilla D, Squadrito F, Serrano M, Campo G M, Squadrito G, Arlotta M, Urna G, Sardella A, Saitta A, Caputi A P

机构信息

Institute of Pharmacology, School of Medicine, University of Messina, Italy.

出版信息

Br J Pharmacol. 1998 Jul;124(6):1293-9. doi: 10.1038/sj.bjp.0701944.

DOI:10.1038/sj.bjp.0701944

PMID:9720803

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC1565499/

Abstract

Antioxidants can exert protective effects in endotoxic shock by either a reduction of the oxidant damage or attenuation of Tumour Necrosis Factor (TNF-alpha) production. 2. Lazaroids are a family of compounds that inhibit lipid peroxidation. Besides, they can also reduce TNF-alpha. U-83836E is a new lazaroid lacking the glucocorticoid ring. 3. Aim of our study was to investigate the effect of U-83836E on TNF-alpha production either in vivo or in vitro. Endotoxic shock was produced in male rats by a single intravenous (i.v.) injection of 20 mg kg(-1) of S. enteritidis lipopolysaccharide (LPS). LPS administration reduced survival rate (0% survival, 72 h after endotoxin administration), decreased mean arterial blood pressure, increased serum and macrophage TNF-alpha and enhanced plasma malonylaldehyde (MAL) levels. Furthermore aortic rings from shocked rats showed a marked hyporeactivity to phenylephrine (PE 1 nM-10 microM). 4. Treatment with U-83836E (7.5, 15 and 30 mg kg(-1), i.v.) 5 min after endotoxin challenge significantly protected against LPS induced lethality (90% survival rate and 80% survival rate 24 h and 72 h after LPS injection respectively, following the highest dose of the drug), reduced hypotension, blunted plasma MAL, decreased serum and macrophage TNF-alpha and restored the hyporeactivity of aortic rings to control values. In vitro LPS stimulation (50 microg ml(-1) for 4 h) significantly increased cytokine production in macrophages (Mphi) harvested from untreated normal rats. Pretreatment with pertussis toxin (PT; 0.1, 1 and 10 ng ml(-1) 4 h before LPS) significantly increased TNF-alpha production. PT effects on these LPS responses were correlated with a PT mediated ADP ribosylation of a 41 kDa protein. U-83836E (50 microM) reduced, in a dose dependent manner, LPS induced TNF-alpha production and inhibited the PT effects on cytokine production and on ADP ribosylation of the protein. 5. Our data suggest that lazaroids may affect the early events associated with LPS receptor mediated activation of a G protein in LPS induced TNF-alpha production. These molecular events may explain, at least in part, the in vivo inhibition of cytokine production and reversal of endotoxic shock.

摘要

抗氧化剂可通过减少氧化损伤或减弱肿瘤坏死因子（TNF-α）的产生，对内毒素休克发挥保护作用。2. 拉扎oids是一类抑制脂质过氧化的化合物。此外，它们还能降低TNF-α。U-83836E是一种新型拉扎oid，缺乏糖皮质激素环。3. 我们研究的目的是调查U-83836E在体内或体外对TNF-α产生的影响。通过单次静脉注射20 mg kg⁻¹肠炎沙门氏菌脂多糖（LPS），在雄性大鼠中诱导内毒素休克。给予LPS降低了存活率（内毒素给药72小时后存活率为0%），降低了平均动脉血压，增加了血清和巨噬细胞TNF-α水平，并提高了血浆丙二醛（MAL）水平。此外，休克大鼠的主动脉环对去氧肾上腺素（PE 1 nM - 10 μM）表现出明显的反应性降低。4. 在内毒素攻击后5分钟，用U-83836E（7.5、15和30 mg kg⁻¹，静脉注射）进行治疗，可显著预防LPS诱导的致死性（分别在LPS注射后24小时和72小时，最高剂量药物治疗后存活率为90%和80%），减轻低血压，降低血浆MAL水平，降低血清和巨噬细胞TNF-α水平，并使主动脉环的反应性恢复至对照值。在体外，LPS刺激（50 μg ml⁻¹，持续4小时）显著增加了从未经处理的正常大鼠采集的巨噬细胞（Mphi）中的细胞因子产生。用百日咳毒素（PT；在LPS处理前4小时给予0.1、1和10 ng ml⁻¹）进行预处理显著增加了TNF-α的产生。PT对这些LPS反应的影响与PT介导的41 kDa蛋白的ADP核糖基化相关。U-83836E（50 μM）以剂量依赖性方式降低LPS诱导的TNF-α产生，并抑制PT对细胞因子产生和蛋白ADP核糖基化的影响。5. 我们的数据表明，拉扎oids可能影响与LPS受体介导的G蛋白激活相关的早期事件，该事件参与LPS诱导的TNF-α产生。这些分子事件可能至少部分解释了体内细胞因子产生的抑制和内毒素休克的逆转。